The present invention relates to new compounds which are derivatives of tryptamine and their analogs, pharmaceutical formulations containing them, and use of the compounds in the manufacture of medicaments for treating various diseases.
Melatonin is the principal hormone secreted by the pineal gland in all vertebrates. In all mammals studied to date, including humans, a nocturnal rise in the production of melatonin by the pineal gland is evident; melatonin production by the body is acutely suppressed by light. Melatonin is involved in the coordination of photoperiod dependent and physiological processes. The ability of the animals or humans to respond to the melatonin signal may depend upon melatonin receptors. Melatonin acts on the CNS to affect neural mechanisms through receptors located in the brain. Additionally, a number of studies indicate the existence of direct effects of melatonin in peripheral organs via peripheral melatonin receptors. Melatonin receptors are present in the heart, lungs, prostate gland, gonads, white blood cells, retina, pituitary, thyroid, kidney, gut and blood vessels. Retention patterns of radioactive-melatonin injected to rats demonstrate melatonin accumulation in the brain, pituitary, lung, heart, gonads and accessory sex organs (Withyachumnamkul et al., Life Sci 12:1757-65, 1986).
The synthesis and secretion of melatonin exhibit a circadian rhythm that changes with the seasons and with age, e.g., pubescence and senescence. There is very strong evidence that melatonin is important for the regulation of a variety of neural and endocrine functions, especially those that exhibit circadian and circannual rhythmicity.
Melatonin has been implicated in many human disorders. Some are known to be linked to chronobiological abnormalities. Melatonin has been administered to re-synchronize circadian rhythms that are out of phase with the local photoperiodical cycle. For example, sleep/wake disorders with rapid crossing of time zones jet lag), or in delayed sleep phase syndrome (DSPS) patients, changes in work shifts, or those experienced by blind people can be treated with melatonin or melatonin analogs (see U.S. Pat. Nos. 4,600,723 and 4,666,086 of Short et al. and U.S. Pat. No. 5,242,941 of Lewy et al.).
However, it appears that melatonin also has direct sedative/hypnotic properties in normal human subjects (e.g., Waldhauser et al., Psychopharmacology, 100: 222-226, 1990; Vollrath et al., Bioscience 29:327-329, 1981: Dollins et al., Proc. Natl. Acad. Sci, 99:1824-1828, 1994, U.S. Pat. No. 5,403,851 of D""Orlando et al). Three melatonin receptor subtypes have been identified so far mt-1, MT-2 and Me11c (Barrett et al., Biol. Signals Recept., 1999, 8: 6-14). MT-2 is localized mainly in the central nervous system and mt-1, localized in the CNS as well as in peripheral organs such as kidney and the urogenital tract (Dubocovich et al., IUPHAR media, London, UK, 187-93, 1998). The presently known subtypes are not sufficient to evaluate the large variety of melatonin effects and additional receptor subtypes await discovery.
Melatonin has been demonstrated in a number of rodent experimental paradigms to have both anxiolytic (Golus and King, Pharmacol. Biochem. Behav., 41:405-408, 1992, Naranjo-Rodriguez et al., Soc. Neurosci. Abst. 18:1167, 1992; Golombek et al., Eur. J. Pharmacol, 237:231-236, 1993) and antiseizure activity (Brallowsky, Electroencephalo. clin. Neurophysiol. 41:314-319, 1976: Farielloet al., Neurology 27:567-570, 1977, Rudeen et al., Epilepsia 21:149-154, 1980; Sugden, J. Pharmacol Exp. Ther. 227:587-591, 1983; Golombek et al., Eur. J. Pharmacol 210:253-258, 1992).
Melatonin is effective in the treatment of cluster headache and migraine (Claustrat et al., Headache, 29:241-4, 1989). Melatonin may play a role in other psychiatric conditions, particularly depression, but also mania and schizophrenia (see Dobocovich xe2x80x9cAntidepressant Agentsxe2x80x9d, U.S. Pat. No. 5,093,352; Miles and Philbrick, Biol. Psychiatry 23:405-425, 1988: Sandyk and Kay, Schizophr. Bull. 16:653-662, 1990). In some instance, psychiatric disorders may have underlying chronobiological etiologies (e.g. seasonal effective disorder) and are definite candidates for melatonin therapy.
Melatonin is involved in the regulation of circadian and circannual changes in body temperature. Administration of exogenous melatonin to humans lowers core body temperature (Strassman et al., J. Appl. Physiol, 71:2178-2182, 1991; Cagnacci et al., J. Clin. Endocrinol. Merab. 75:447-452, 1992). Melatonin may also possess analgesic properties (Sugden, J. Pharmacol. Exp. Ther. 227:587-591, 1983). Therefore, melatonin-like compounds may be useful as an alternative to non-steroidal anti-inflammatory, anti-pyretic drugs, such as aspirin, acetaminophen and ibuprofen.
It is known that melatonin levels decrease with advancing age (Sack et al., J. Pineal Res. 4:379-388, 1986; Waldhauser et al., J. Clin. Endocrinol. Metab., 66:648-652, 1988; Van Coavorden et al., Am. J. Physiol. 260:E651-661, 1991) which may contribute to some disorders, Neurodegenerative diseases often associated with aging, such as Alzheimer""s and Parkinson""s diseases, may be treated with melatoninergic compounds (Maurizi, Med. Hypotheses 31:233-242, 1990; Sandyk, Int. J. Neurosci. 50:37-53, 1990; Skene et al., Brain Rev. 528:170-174, 1990).
Sleep disorders in the elderly have been shown to respond to melatonin treatment (Garfinkel et al., Lancet, 346:541-543, 1995, U.S. Pat. No. 5,498,423 of Zisapel). Soporific effects of melatonin (0.3-240 mg) have been reported in humans following intravenous, intranasal and oral administration. Apart from its soporific effects, exogenous melatonin may affect sleep via its phase-resetting action on the biological clock. Melatonin administration advanced sleep in delayed sleep syndrome patients, and synchronized sleep to the day-night cycles in blind subjects. The efficacy of melatonin (0.3-5 mg/os) for treatment of insomnia has been demonstrated in studies performed mainly with elderly patients, patients treated with atenolol and chronic heart patients, most of which patients have low or distorted melatonin rhythms. In some of these studies, formulations which release melatonin throughout the night were used, in order to circumvent fast clearance of the hormone and to mimic its endogenous profile (Nutrition, 1998, 14: 1-2; The Aging Male, 1998, 1: 1-8). Melatonin, 3 mg, given to patients with sleep disorders and dementia for 21 days, significantly augmented sleep quality and decreased the number of wakening episodes, while agitated behavior at night (sundowning) decreased significantly (Biol. Signals Recept. 1999, 8(1-2): 126-31).
We have recently found that melatonin treatment may be beneficial not only for improving sleep quality, but may also lead to an improvement in the general state of diabetic patients, as indicated by the decrease in HbA1c levels after long-term treatment.
Daily melatonin supplementation to male Sprague-Dawley rats, starting at middle age (10 months) and continuing into old age (22 months) via the drinking water at a dosage of 4 xcexcg/ml, restored the age-related elevated levels of relative (% of body weight) retroperitoneal and epididymal fat, as well as plasma insulin and leptin levels to youthful (4 month) levels (Rasmussen et al., Endocrinology, 1999, 140(2): 1009-12).
Even osteoporosis may have a melatoninergic component (Sandyk et al., Int. J. Neurosci. 62:215-225, 1992). In fact, melatonin has been suggested to be an anti-aging, anti-stress hormone (Armstrong and Redman, Med. Hypotheses 34:300-309, 1991; Reiter, Bioassays, 14:169-175, 1992). This may be due to its action as a free radical scavenger (Pooggeler et al., J. Pineal Res. 14:151-168, 1993) or its interaction with the immune system (Maestroni and Conti, J. Neuroimmun. 28:167-176 1990; Fraschini et al., Acta. Oncol. 29:775-776 1990, Guerrero and Reiter, Endocr. Res. 18:91-113, 1992). Melatonin may protect from ischemic stroke (Cho et al., Brain Research 755:335-338, 1997), decrease cell-death in Alzheimer""s disease (Pappola et al., J Neurosci 17:1683-90, 1997) and lower the risk of SIDS in young infants with low endogenous melatonin levels (Israel Patents Nos. 115861/2 and U.S Pat. No. 5,500,225 of Laudon et al).
Related to the above, are the findings that melatonin has oncostatic properties in a variety of cancers, the most studied being its effect on estrogen receptor positive breast cancers (Blasak and Hill, J. Neural. Transm. Suppl. 21:433-449, 1986; Gonzalez et al. Melanoma. Res.1:237-243, 1991; Lissoni et al. Eur. J. Cancer 29A:185-189, 1993; Shellard et al. Br. J. Cancer 60:288-290, 1989; Philo and Berkowitz, J. Urol. 139:1099-1102, 1988; see U.S. Pat. No. 5,196,435 of Clemens et al. and U.S. Pat. No. 5,272,141 of Fraschini et al.). It is also possible that melatonin has antiproliferative effects on noncancerous cells as well and may be of use to treat benign tumors and proliferative diseases such as BPH (U.S. Pat. No. 5,750,557 and European Patent No. EP 0565296B of Zisapel) and Psoriasis.
A major portion of research on melatonin has been devoted to studying is effects on reproduction, particularly in seasonally breeding species (such as hamsters and sheep), in which melatonin is known to regulate fertility and puberty, hibernation, and coat color. These effects have obvious significance for animal husbandry use. Reproductive endocrine uses in humans for melatonin include: contraceptive and fertility agents, treatment for precocious puberty, treatment for premenstrual syndrome and hyperprolactinemia (Pevre et al., J. Clin. Endocrinol. Metab. 47:1383-1386, 1978; Purry et al., Am. J. Psychiatry 144:762-766, 1987: Waldhauser et al., Clin. Endocrinol. Metab. 73:793-796, 1991; Bispink et al., Pineal Res. 8:97-106, 1990; Cagnacci et al., J. Clin. Endocrinol. Metab. 73:210-220, 1991; Voordouw et al., J. Clin. Endocrinol. Metab. 74:107-108, 1992; see U.S. Pat. Nos. 4,855,305 and 4,945,103 of Cohen et al., and U.S. Pat. No. 5,272,141 of Fraschini et al.). It is likely that melatonin compounds may also be useful in other endocrine conditions, particularly those involving growth hormone (Cramer et al., Arzeneim-Forsch, 26:1076-1078, 1976; Wright et al., Clin. Endocrinol. 24:375-382, 1986; Paccotti et al., Chronobiologica 15:279-288, 1988; Valcavi et al., Clin. Endocrinol. 39:139-199, 1993). Melatonin may serve to reduce prostate enlargement (see above-cited U.S. and EP patents of Zisapel) Orally administered melatonin to castrated juvenile rats inhibited the androgen-dependent growth of the ventral prostate and the seminal vesicles. (Gilad et al., J. of Urol. 159:1069-73, 1998). Recently, we have demonstrated high affinity melatonin receptors in the human benign prostate epithelial cells, which may affect cell growth and viability (Endocrinology, 137:1412-17, 1996).
In addition to the pineal gland, the eye also synthesizes melatonin. Recently melatonin has been implicated in the control of intraocular pressure and may be of use in glaucoma (Samples et al., Curr, Eye, Res. 7:649-653, 1988; Rhode et al., Ophthalmic. Res. 25:10-15, 1993).
The kidney also expresses melatonin receptors and melatonin has been shown to affect vasopressin and urine excretion (Song et al., FASEB J 11:93-100, 1997, Yasin et al., Brain Res. Bull 39:1-5, 1997).
It is clear that there exists a broad range of therapeutic uses for melatonin. Accordingly it is of continuing interest to identify novel compounds that interact with melatoninergic system as potential therapeutic agents. These compounds may offer longer duration, selective localization and greater efficacy to those of melatonin.
Novel compounds related to melatonin, but with pharmacological or pharmacokinetic profiles different from melatonin, are likely to be important new pharmaceuticals, For examples, see U.S. Pat. No. 5,403,851 which discloses the use of substituted tryptamines, phenylalkylamines and related compounds, in order to treat number of pharmaceutical indications including sleep disorders, endocrine indications, immune-system disorders etc. PCT Patent Application No. WO 87/00432 describes compositions, for treating or preventing psoriasis, which contain melatonin or related compounds. European Patent Application No. 0330625A2 discloses the production of melatonin and analogs thereof, for various therapeutic purposes, including the administration of melatonin in combination with an azidothymidine for the treatment of AIDS. Melatonin analogs based on the bioisosteric properties naphthalenic ring and the indole ring has been disclosed in J. Med. Chem. 1992. 35:1484-1485, EP 662471 A2 950712 of Depreux et al., WO 9529173 A1 951102 of Ladlow et al., U.S. Pat. No. 5,151,446 of Horn et al., U.S. Pat. No. 5,194,614 of Adrieux et al. and U.S. Pat. No. 5,276,051 of Lesieur et al.
Inhibition by melatonin of dopamine release from specific brain areas has been demonstrated in vitro in rats (Zisapel et al., Brain Res 1982; 246(1):161-3; Brain Res 1982;246(1):161-3) sheep and hamsters (Malpaux et al. Reprod Nutr Dev 1999;39(3):355-66). In addition, melatonin was able to reduce excitability of nigrostriatal neurons (Escames etal Neuroreport 1996;7(2):597-600) and increase the affinity of D2 dopamine receptors in the rat striatum (Hamdi Life Sci 1998;63:2115-20). It may therefore treat disorders associated with increased dopamine release or dopamine supersensitivity, e.g. for tardivexe2x80x94dyskinesia, or cocaine addiction.
Melatonin antagonist are also of potential therapeutic use. A reduction in nigrostriatal dopaminergic activity as that caused by melatonin could lead to worsening of parkinsonian side effects and akathisia, as is indeed supported by findings in animal models of Parkinson disease (Willis and Armstrong Brain Res Brain Res Rev 1998; 27(3):177-242). Melatonin antagonists may thus be helpful to prevent the effects of endogenous melatonin in Parkinson""s disease. Melatonin antagonists may also be helpful in preventing fatigue and sleepiness of shift workers caused by the increase in endogenous melatonin at night; in blind persons that are not synchronized with the environmental light dark cycle, in delayed sleep phase syndrome patients who secrete melatonin during daytime and in jet lag.
There is evidence suggesting both melatonin agonists and antagonists_would be of potential therapeutic use for a variety of maladies and conditions. The present invention addresses the need for more therapeutically selective compounds than melatonin.
The compounds N-(2,4-dinitrophenyl)-5-methoxytryptamine (xe2x80x9cML-23xe2x80x9d) and N-(2,4-dinitrophenyl)-2-iodo-5-methoxytryptamine, are known to have antagonistic effects on melatonin (Zisapel et al 1989, U.S. Pat. No. 4,880,826, Laudon et al, J Endocrinol. 1988; 116:43-53, Oaknin-Bendahan et al, Neuroreport 1995 27;6:785-8, Nordio et al Proc Soc Exp Biol Med 1989; 191:321-5, Zisapel et al, Eur J Pharmacol 1987: 136, 259-60). To the best of the present inventors"" knowledge, it has never been previously suggested that other N-(2,4-dinitrophenyl)-5-methoxytryptamines, or their ether or thioether analogs, might have potential use for interacting with the melatoninergic system.
The entire contents of the above-cited patents, patent applications and literature articles are deemed to be incorporated herein by reference.
In one aspect, the present provides compounds having the formula (I): 
and their acid addition salts where the compounds are basic, wherein:
each of R1, R2 and R3 is independently selected from among hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, NRxe2x80x2Rxe2x80x3, N(Rxe2x80x2)C(:O)Ro, nitro, aryl, aryl-C1-4 alkyl, or aryl-C1-4 alkoxy, Ro is C1-4 alkyl or aryl, and each of Rxe2x80x2 and Rxe2x80x3 is independently H or C1-4 alkyl, or Rxe2x80x2xe2x95x90Rxe2x80x3xe2x95x90ClCH2CH2, or NRxe2x80x2Rxe2x80x3 constitutes a saturated heterocyclic ring containing 3-8 ring members; m is 0-4; t is 0-3; X is NH, Nxe2x80x94C1-4 alkyl, O or S; provided that X is not NH when simultaneously (R1)m is 5-methoxy, R2 is H or I and t=0.
In the above definition, xe2x80x9carylxe2x80x9d is the monovalent residue of an unsubstituted or substituted aromatic nucleus, preferably a benzene ring, but it may also be e.g., another monovalent carbocyclic aryl residue such as naphthyl, or the monovalent residue of a heterocyclic aromatic ring such as furan, thiophene, pyrrole, pyridine, benzopyran or benzothiophene. When aryl is substituted, the substituent may be, e.g., one or more of hydroxy, C1-4-alkoxy, halogen, cyano, nitro, carboxylic acid, ester or amide, sulfonic acid, ester or amide, sulfone, sulfoxide or halogenated C1-4-alkyl such as chloro- or dichloro-methyl or CF3, amino, mono(C1-4-alkyl)amino, di(C1-4-alkyl)amino, or C1-4-alkyl.
In another aspect, the invention provides a pharmaceutical formulation which comprises at least one pharmaceutically acceptable diluent, preservative, solubilizer, emulsifier, adjuvant, and/or carrier, and at least one member of the group consisting of the compounds of the invention as defined above and pharmaceutically acceptable salts thereof.
In yet another aspect, the invention provides use of at least one member of the group consisting of the compounds of the invention as defined above and pharmaceutically acceptable salts thereof, in the manufacture of a medicament for interacting with the melatoninergic system, e.g. a medicament for use in animal breeding, or for the prevention or treatment of prostate conditions, impotence, cardiovascular disorders, central nervous system and psychiatric disorders, chronobiological-based disorders endocrine indications, neoplastic conditions, immune system, conditions associated with senescence, ophthalmological diseases, cluster headache and migraine.
In still another aspect, the invention provides a method for treating a medical condition in a mammal (human or non-human) which is susceptible to alleviation by treatment with a medicament which interacts with the melatoninergic system, which comprises treating such condition with an effective amount of at least one member of the group consisting of the compounds defined in claim 1 and pharmaceutically acceptable salts thereof.